tbuckley/cabot-search huggingface dataset:
Uncovering Footprints of Natural Selection Through Spectral Analysis of Genomic Summary Statistics
Authors: Sandipan Paul Arnab, Md Ruhul Amin, Michael DeGiorgio
Journal: Molecular Biology and Evolution (2023)

Natural selection leaves a spatial pattern along the genome, with a haplotype distribution distortion near the selected locus that fades with distance. Evaluating the spatial signal of a population-genetic summary statistic across the genome allows for patterns of natural selection to be distinguished from neutrality. Considering the genomic spatial distribution of multiple summary statistics is expected to aid in uncovering subtle signatures of selection. In recent years, numerous methods have been devised that consider genomic spatial distributions across summary statistics, utilizing both classical machine learning and deep learning architectures. However, better predictions may be attainable by improving the way in which features are extracted from these summary statistics. We apply wavelet transform, multitaper spectral analysis, and S-transform to summary statistic arrays to achieve this goal. Each analysis method converts one-dimensional summary statistic arrays to two-dimensional images of spectral analysis, allowing simultaneous temporal and spectral assessment. We feed these images into convolutional neural networks and consider combining models using ensemble stacking. Our modeling framework achieves high accuracy and power across a diverse set of evolutionary settings, including population size changes and test sets of varying sweep strength, softness, and timing. A scan of central European whole-genome sequences recapitulated well-established sweep candidates and predicted novel cancer-associated genes as sweeps with high support. Given that this modeling framework is also robust to missing genomic segments, we believe that it will represent a welcome addition to the population-genomic toolkit for learning about adaptive processes from genomic data.
Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP
Authors: Jennifer K. Litton, Meredith M. Regan, Lajos Pusztai, Hope S. Rugo, Sara M. Tolaney, Elizabeth Garrett-Mayer, Laleh Amiri-Kordestani, Reva K. Basho, Ana F. Best, Jean-Francois Boileau, Carsten Denkert, Jared C. Foster, Nadia Harbeck, Heather A. Jacene, Tari A. King, Ginny Mason, Ciara C. O'Sullivan, Tatiana M. Prowell, Andrea L. Richardson, Karla A. Sepulveda, Mary Lou Smith, Judy A. Tjoe, Gulisa Turashvili, Wendy A. Woodward, Lynn Pearson Butler, Elena I. Schwartz, Larissa A. Korde
Journal: Journal of Clinical Oncology (2023)

The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points.
Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer
Authors: Sachin R Jhawar, Shang-Jui Wang, Aditya Thandoni, Praveen K Bommareddy, Jenna H Newman, Eileena F Giurini, Amanda L Marzo, Timothy M Kuzel, Vineet Gupta, Jochen Reiser, Preston Daniels, Devora Schiff, Darrion Mitchell, Nicole R LeBoeuf, Christopher Simmons, Sharad Goyal, Ahmed Lasfar, Jose A Guevara-Patino, Bruce G Haffty, Howard L Kaufman, Ann W Silk, Andrew Zloza
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes. Methods To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy. Results Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically ‘cold’ tumors to ‘hot’, via a CD8+ T cell-dependent and IL-1α-dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for &gt;44 months since study entry. Conclusions Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers.
Cardiac Interventions in Patients With Active, Advanced Solid and Hematologic Malignancies
Authors: Darryl P. Leong, Filipe Cirne, Nazanin Aghel, Rocio C. Baro Vila, Germano D. Cavalli, Peter M. Ellis, Jeff S. Healey, Richard Whitlock, Dina Khalaf, Hira Mian, Sanjit S. Jolly, Shamir R. Mehta, Susan Dent
Journal: JACC CardioOncology (2023)

Invasive cardiac interventions are recommended to treat ST-segment elevation myocardial infarction, non-ST-segment elevation acute coronary syndromes, multivessel coronary disease, severe symptomatic aortic stenosis, and cardiomyopathy. These recommendations are based on randomized controlled trials that historically included few individuals with active, advanced malignancies. Advanced malignancies represent a significant competing risk for mortality, and there is limited evidence to inform the risks and benefits of invasive cardiac interventions in affected patients. We review the benefit conferred by invasive cardiac interventions; the periprocedural considerations; the contemporary survival expectations of patients across several types of active, advanced malignancy; and the literature on cardiovascular interventions in these populations. Our objective is to develop a rational framework to guide clinical recommendations on the use of invasive cardiac interventions in patients with active, advanced cancer.
Endoplasmic Reticulum Selective Autophagy Alleviates Anthracycline-Induced Cardiotoxicity
Authors: Shun Nakagama, Yasuhiro Maejima, Qintao Fan, Yuka Shiheido-Watanabe, Natsuko Tamura, Kensuke Ihara, Tetsuo Sasano
Journal: JACC CardioOncology (2023)

The administration of anthracycline drugs induces progressive and dose-related cardiac damage through several cytotoxic mechanisms, including endoplasmic reticulum (ER) stress. The unfolded protein response plays a crucial role for mitigating misfolded protein accumulation induced by excessive ER stress.We aimed to clarify whether endoplasmic reticulum-selective autophagy machinery (ER-phagy) serves as an alternative system to protect cardiomyocytes from ER stress caused by anthracycline drugs.Primary cultured cardiomyocytes, H9c2 cell lines, and cardiomyocyte-specific transgenic mice, all expressing ss-RFP-GFP-KDEL proteins, were used as ER-phagy reporter models. We generated loss-of-function models using RNA interference or gene-trap mutagenesis techniques. We assessed phenotypes and molecular signaling pathways using immunoblotting, quantitative polymerase chain reaction, cell viability assays, immunocytochemical and histopathological analyses, and cardiac ultrasonography.The administration of doxorubicin (Dox) activated ER-phagy in ss-RFP-GFP-KDEL-transduced cardiomyocytes. In addition, Dox-induced cardiomyopathy models of ER-phagy reporter mice showed marked activation of ER-phagy in the myocardium compared to those of saline-treated mice. Quantitative polymerase chain reaction analyses revealed that Dox enhanced the expression of cell-cycle progression gene 1 (CCPG1), one of the ER-phagy receptors, in H9c2 cells. Ablation of CCPG1 in H9c2 cells resulted in the reduced ER-phagy activity, accumulation of proapoptotic proteins, and deterioration of cell survival against Dox administration. CCPG1-hypomorphic mice developed more severe deterioration in systolic function in response to Dox compared to wild-type mice.Our findings highlight a compensatory role of CCPG1-driven ER-phagy in reducing Dox toxicity. With further study, ER-phagy may be a potential therapeutic target to mitigate Dox-induced cardiomyopathy.
Clinical and Molecular Features of Long-term Response to Immune Checkpoint Inhibitors in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Rohit Thummalapalli, Biagio Ricciuti, Chaitanya Bandlamudi, Daniel Muldoon, Hira Rizvi, Arielle Elkrief, Jia Luo, Joao V. Alessi, Federica Pecci, Giuseppe Lamberti, Alessandro Di Federico, Lingzhi Hong, Jianjun Zhang, John V. Heymach, Don L. Gibbons, Andrew J. Plodkowski, Vignesh Ravichandran, Mark T.A. Donoghue, Chad Vanderbilt, Marc Ladanyi, Charles M. Rudin, Mark G. Kris, Gregory J. Riely, Jamie E. Chaft, Matthew D. Hellmann, Natalie I. Vokes, Mark M. Awad, Adam J. Schoenfeld
Journal: Clinical Cancer Research (2023)

We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICI), and how these might differ from features predictive of short-term response (STR).
A Novel <i>HOXA10</i>-Associated 5-Gene–Based Prognostic Signature for Stratification of Short-term Survivors of Pancreatic Ductal Adenocarcinoma
Authors: Sophia G. Kisling, Pranita Atri, Ashu Shah, Jesse L. Cox, Sunandini Sharma, Lynette M. Smith, Dario Ghersi, Surinder K. Batra
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Despite the significant association of molecular subtypes with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), few efforts have been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes. Experimental Design: We analyzed the transcriptomic profiles of treatment-naïve surgically resected short-term survivor (STS) and long-term survivor (LTS) tumors (GSE62452) for expression and survival, followed by validation in several datasets. These results were corroborated by IHC analysis of PDAC-resected STS and LTS tumors. The mechanism of this differential survival was investigated using CIBERSORT and pathway analyses. Results: We identified a short-surviving prognostic subtype of PDAC with a high degree of significance (P = 0.018). One hundred thirty genes in this novel subtype were found to be regulated by a master regulator, homeobox gene HOXA10, and a 5-gene signature derived from these genes, including BANF1, EIF4G1, MRPS10, PDIA4, and TYMS, exhibited differential expression in STSs and a strong association with poor survival. This signature was further associated with the proportion of T cells and macrophages found in STSs and LTSs, demonstrating a potential role in PDAC immunosuppression. Pathway analyses corroborated these findings, revealing that this HOXA10-driven prognostic signature is associated with immune suppression and enhanced tumorigenesis. Conclusions: Overall, these findings reveal the presence of a HOXA10-associated prognostic subtype that can be used to differentiate between STS and LTS patients of PDAC and inform on the molecular interactions that play a role in this poor prognosis.
Histone Variants and Their Chaperones in Hematological Malignancies
Authors: Ecem Kirkiz, Oliver Meers, Florian Grebien, Marcus Buschbeck
Journal: HemaSphere (2023)

Epigenetic regulation occurs on the level of compacting DNA into chromatin. The functional unit of chromatin is the nucleosome, which consists of DNA wrapped around a core of histone proteins. While canonical histone proteins are incorporated into chromatin through a replication-coupled process, structural variants of histones, commonly named histone variants, are deposited into chromatin in a replication-independent manner. Specific chaperones and chromatin remodelers mediate the locus-specific deposition of histone variants. Although histone variants comprise one of the least understood layers of epigenetic regulation, it has been proposed that they play an essential role in directly regulating gene expression in health and disease. Here, we review the emerging evidence suggesting that histone variants have a role at different stages of hematopoiesis, with a particular focus on the histone variants H2A, H3, and H1. Moreover, we discuss the current knowledge on how the dysregulation of histone variants can contribute to hematopoietic malignancies.
Time Trends in the Incidence of Diabetic Ketoacidosis Leading to Hospital Admission Among Adults With Type 1 Diabetes: A Nationwide Danish Register Study
Authors: Elisabeth B. Stougaard, Hanan Amadid, Esben Søndergaard, Bendix Carstensen, Marit E. Jørgensen, Kirsten Nørgaard, Peter Rossing, Frederik Persson, Dorte Vistisen
Journal: Diabetes Care (2023)

OBJECTIVE Diabetic ketoacidosis (DKA) is a life-threatening but preventable complication in people with type 1 diabetes. We aimed to quantify the incidence of DKA according to age and describe the time trend of DKA among adults with type 1 diabetes in Denmark. RESEARCH DESIGN AND METHODS Individuals aged ≥18 years with type 1 diabetes were identified from a nationwide Danish diabetes register. Hospital admissions due to DKA were ascertained from the National Patient Register. The follow-up period was from 1996 to 2020. RESULTS The cohort consisted of 24,718 adults with type 1 diabetes. The incidence rate of DKA per 100 person-years (PY) decreased with increasing age for both men and women. From 20 to 80 years of age, the DKA incidence rate decreased from 3.27 to 0.38 per 100 PY. From 1996 to 2008, the incidence rate of DKA increased for all age-groups, with a subsequent minor decrease in incidence rate until 2020. From 1996 to 2008, the incidence rates increased from 1.91 to 3.77 per 100 PY for a 20-year-old individual and from 0.22 to 0.44 per 100 PY for an 80-year-old individual living with type 1 diabetes. From 2008 to 2020 the incidence rates decreased from 3.77 to 3.27 and from 0.44 to 0.38 per 100 PY, respectively. CONCLUSIONS The incidence rates of DKA are declining for all ages, with an overall decline from 2008 for both men and women. This likely reflects improved diabetes management for individuals with type 1 diabetes in Denmark.
GABAergic signaling between enteric neurons and intestinal smooth muscle promotes innate immunity and gut defense in Caenorhabditis elegans
Authors: Junqiang Liu, Pei Zhang, Zhongfan Zheng, Muhammad Irfan Afridi, Shan Zhang, Zhiqing Wan, Xiumei Zhang, Lukas Stingelin, Yirong Wang, Haijun Tu
Journal: Immunity (2023)
Re: Toni K. Choueiri, Thomas Powles, Laurence Albiges, et al. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med 2023;388:1767–78
Authors: Clara Cerrato, Benjamin Pradere, Maria Carmen Mir
Journal: European Urology (2023)
Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer’s disease
Authors: Yasuteru Inoue, Francis Shue, Guojun Bu, Takahisa Kanekiyo
Journal: Molecular Neurodegeneration (2023)

Abstract Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer’s disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood–brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD.
Towards a novel clinical outcome assessment for systemic lupus erythematosus: first outcomes of an international taskforce
Authors: Kathryn Connelly, Laura E. Eades, Rachel Koelmeyer, Darshini Ayton, Vera Golder, Rangi Kandane-Rathnayake, Kate Gregory, Hermine Brunner, Laurie Burke, Laurent Arnaud, Anca Askanase, Cynthia Aranow, Ed Vital, Guillermo Pons-Estel, Khadija Dantata, Jeanette Andersen, Alain Cornet, Joy Buie, Ying Sun, Yoshiya Tanaka, Lee Simon, Youmna Lahoud, Alan Friedman, Kenneth Kalunian, Qing Zuraw, Victoria Werth, Sandra Garces, Eric F. Morand, Alessandro Sorrentino, Anna Stevens, Catherine Barbey, Elaine Karis, Eric Morand, Erika Noss, Eve MD Smith, George Stojan, Jorge Ross Teres, Justine Maller, Maya Hojnik, Nikolay Delev, Laura Eades, Maria Dall’Era, Patrick Marquis, Richard Furie, Ronald van Vollenhoven, Tim Coulom, Cailin Sibley, Christian Stach, Cristina Vazquez-Mateo, Eric Zollars, Heath Guay, Hussein Al-Mossawi, Joan Merrill, Jorge Ross Terres, Karen Costenbader, Maria Silk, Marta Mosca, Nicki Bush, Subhashis Banerjee, Thierry Sornasse, Blanca Rubio, Dalila Tremarias, Dalilah Kalla, Gonzalo Tobar Carrizo, Imasha Adisa, Shiori Nagamori, Sibongile Komati, Stephanie Scoggins, Susanne Udengaard Gydesen, Toni Grimes, Vinita Haroun, Zoe Karakikla-Mitsa, Ann Eldred, Bianca Fedriz, Catharine Lindholm, Charlotte Lupton, Dennis Grasela, Erik Thomas, Maria Juarez, Nitin Kumar, Oliver Guenther, Samantha Pomponi, Sanjeev Roy, Shelly Kafka, Thomas Morel, Yulia Pincus
Journal: Nature Reviews Rheumatology (2023)
Minimally invasive techniques for lateral maxillary sinus floor elevation: small lateral window and one-stage surgery—a 2–5-year retrospective study
Authors: Shaojingya Gao, Yao Jiang, Yangxue Yao, Songhang Li, Xiaoxiao Cai
Journal: International Journal of Oral Science (2023)

Abstract This study aimed to introduce a minimally invasive technique for maxillary sinus floor elevation using the lateral approach (lSFE) and to determine the factors that influence the stability of the grafted area in the sinus cavity. Thirty patients (30 implants) treated with lSFE using minimally invasive techniques from 2015 to 2019 were included in the study. Five aspects of the implant (central, mesial, distal, buccal, and palatal bone heights [BHs]) were measured using cone-beam computed tomography (CBCT) before implant surgery, immediately after surgery (T0), 6 months after surgery (T1), and at the last follow-up visit (T2). Patients’ characteristics were collected. A small bone window (height, (4.40 ± 0.74) mm; length, (6.26 ± 1.03) mm) was prepared. No implant failed during the follow-up period (3.67 ± 1.75) years. Three of the 30 implants exhibited perforations. Changes in BH of the five aspects of implants showed strong correlations with each other and BH decreased dramatically before second-stage surgery. Residual bone height (RBH) did not significantly influence BH changes, whereas smoking status and type of bone graft materials were the potentially influential factors. During the approximate three-year observation period, lSFE with a minimally invasive technique demonstrated high implant survival rate and limited bone reduction in grafted area. In conclusion, lSFE using minimally invasive techniques was a viable treatment option. Patients who were nonsmokers and whose sinus cavity was filled with deproteinized bovine bone mineral (DBBM) had significantly limited bone resorption in grafted area.
CARE as a wearable derived feature linking circadian amplitude to human cognitive functions
Authors: Shuya Cui, Qingmin Lin, Yuanyuan Gui, Yunting Zhang, Hui Lu, Hongyu Zhao, Xiaolei Wang, Xinyue Li, Fan Jiang
Journal: npj Digital Medicine (2023)

Circadian rhythms are crucial for regulating physiological and behavioral processes. Pineal hormone melatonin is often used to measure circadian amplitude but its collection is costly and time-consuming. Wearable activity data are promising alternative, but the most commonly used measure, relative amplitude, is subject to behavioral masking. In this study, we firstly derive a feature named circadian activity rhythm energy (CARE) to better characterize circadian amplitude and validate CARE by correlating it with melatonin amplitude (Pearson's r = 0.46, P = 0.007) among 33 healthy participants. Then we investigate its association with cognitive functions in an adolescent dataset (Chinese SCHEDULE-A, n = 1703) and an adult dataset (UK Biobank, n = 92,202), and find that CARE is significantly associated with Global Executive Composite (β = 30.86, P = 0.016) in adolescents, and reasoning ability, short-term memory, and prospective memory (OR = 0.01, 3.42, and 11.47 respectively, all P < 0.001) in adults. Finally, we identify one genetic locus with 126 CARE-associated SNPs using the genome-wide association study, of which 109 variants are used as instrumental variables in the Mendelian Randomization analysis, and the results show a significant causal effect of CARE on reasoning ability, short-term memory, and prospective memory (β = -59.91, 7.94, and 16.85 respectively, all P < 0.0001). The present study suggests that CARE is an effective wearable-based metric of circadian amplitude with a strong genetic basis and clinical significance, and its adoption can facilitate future circadian studies and potential intervention strategies to improve circadian rhythms and cognitive functions.
British Thoracic Society Guideline for pleural disease
Authors: Mark E Roberts, Najib M Rahman, Nick A Maskell, Anna C Bibby, Kevin G Blyth, John P Corcoran, Anthony Edey, Matthew Evison, Duneesha de Fonseka, Rob Hallifax, Susan Harden, Iain Lawrie, Eric Lim, David J McCracken, Rachel Mercer, Eleanor K Mishra, Andrew G Nicholson, Farinaz Noorzad, Kirstie Opstad, Maria Parsonage, Andrew E Stanton, Steven Walker
Journal: Thorax (2023)

### Spontaneous pneumothorax #### Acute management for spontaneous pneumothorax ##### Recommendations ##### Good practice points #### Optimal management after the resolution of a first episode of pneumothorax ##### Good practice points #### Optimal management for spontaneous pneumothorax and ongoing air leak ##### Good practice point